GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil

Fipronil (FPN) is a worldwide-used neurotoxic insecticide, targeting, and blocking GABAA receptors (GABAARs). Beyond its efficiency on insect GABAARs, FPN causes neurotoxic effects in humans and mammals. Here, we investigated the mode of action of FPN on mammalian α6-containing GABAARs to understand...

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Autores principales:	Zineb Soualah, Antoine Taly, Lucille Crespin, Ophélie Saulais, Daniel Henrion, Claire Legendre, Hélène Tricoire-Leignel, Christian Legros, César Mattei
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	fipronil GABAA receptor synaptic/extrasynaptic receptor voltage-clamp recording cerebellum Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/ceb9ff75ecb04493bc3f8dee993d1132
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spelling	oai:doaj.org-article:ceb9ff75ecb04493bc3f8dee993d11322021-12-01T13:16:25ZGABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil1662-453X10.3389/fnins.2021.768466https://doaj.org/article/ceb9ff75ecb04493bc3f8dee993d11322021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnins.2021.768466/fullhttps://doaj.org/toc/1662-453XFipronil (FPN) is a worldwide-used neurotoxic insecticide, targeting, and blocking GABAA receptors (GABAARs). Beyond its efficiency on insect GABAARs, FPN causes neurotoxic effects in humans and mammals. Here, we investigated the mode of action of FPN on mammalian α6-containing GABAARs to understand its inhibitory effects on GABA-induced currents, as a function of the synaptic or extrasynaptic localization of GABAARs. We characterized the effects of FPN by electrophysiology using Xenopus oocytes which were microtransplanted with cerebellum membranes or injected with α6β3, α6β3γ2S (synaptic), and α6β3δ (extrasynaptic) cDNAs. At micromolar concentrations, FPN dose-dependently inhibited cerebellar GABA currents. FPN acts as a non-competitive antagonist on ternary receptors. Surprisingly, the inhibition of GABA-induced currents was partial for extra-synaptic (α6β3δ) and binary (α6β3) receptors, while synaptic α6β3γ2S receptors were fully blocked, indicating that the complementary γ or δ subunit participates in FPN-GABAAR interaction. FPN unexpectedly behaved as a positive modulator on β3 homopentamers. These data show that FPN action is driven by the subunit composition of GABAARs—highlighting the role of the complementary subunit—and thus their localization within a physiological synapse. We built a docking model of FPN on GABAARs, which reveals two putative binding sites. This is consistent with a double binding mode of FPN on GABAARs, possibly one being of high affinity and the other of low affinity. Physiologically, the γ/δ subunit incorporation drives its inhibitory level and has important significance for its toxicity on the mammalian nervous system, especially in acute exposure.Zineb SoualahAntoine TalyAntoine TalyLucille CrespinOphélie SaulaisDaniel HenrionClaire LegendreHélène Tricoire-LeignelChristian LegrosCésar MatteiFrontiers Media S.A.articlefipronilGABAA receptorsynaptic/extrasynaptic receptorvoltage-clamp recordingcerebellumNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	fipronil GABAA receptor synaptic/extrasynaptic receptor voltage-clamp recording cerebellum Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	fipronil GABAA receptor synaptic/extrasynaptic receptor voltage-clamp recording cerebellum Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Zineb Soualah Antoine Taly Antoine Taly Lucille Crespin Ophélie Saulais Daniel Henrion Claire Legendre Hélène Tricoire-Leignel Christian Legros César Mattei GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil
description	Fipronil (FPN) is a worldwide-used neurotoxic insecticide, targeting, and blocking GABAA receptors (GABAARs). Beyond its efficiency on insect GABAARs, FPN causes neurotoxic effects in humans and mammals. Here, we investigated the mode of action of FPN on mammalian α6-containing GABAARs to understand its inhibitory effects on GABA-induced currents, as a function of the synaptic or extrasynaptic localization of GABAARs. We characterized the effects of FPN by electrophysiology using Xenopus oocytes which were microtransplanted with cerebellum membranes or injected with α6β3, α6β3γ2S (synaptic), and α6β3δ (extrasynaptic) cDNAs. At micromolar concentrations, FPN dose-dependently inhibited cerebellar GABA currents. FPN acts as a non-competitive antagonist on ternary receptors. Surprisingly, the inhibition of GABA-induced currents was partial for extra-synaptic (α6β3δ) and binary (α6β3) receptors, while synaptic α6β3γ2S receptors were fully blocked, indicating that the complementary γ or δ subunit participates in FPN-GABAAR interaction. FPN unexpectedly behaved as a positive modulator on β3 homopentamers. These data show that FPN action is driven by the subunit composition of GABAARs—highlighting the role of the complementary subunit—and thus their localization within a physiological synapse. We built a docking model of FPN on GABAARs, which reveals two putative binding sites. This is consistent with a double binding mode of FPN on GABAARs, possibly one being of high affinity and the other of low affinity. Physiologically, the γ/δ subunit incorporation drives its inhibitory level and has important significance for its toxicity on the mammalian nervous system, especially in acute exposure.
format	article
author	Zineb Soualah Antoine Taly Antoine Taly Lucille Crespin Ophélie Saulais Daniel Henrion Claire Legendre Hélène Tricoire-Leignel Christian Legros César Mattei
author_facet	Zineb Soualah Antoine Taly Antoine Taly Lucille Crespin Ophélie Saulais Daniel Henrion Claire Legendre Hélène Tricoire-Leignel Christian Legros César Mattei
author_sort	Zineb Soualah
title	GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil
title_short	GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil
title_full	GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil
title_fullStr	GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil
title_full_unstemmed	GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil
title_sort	gabaa receptor subunit composition drives its sensitivity to the insecticide fipronil
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/ceb9ff75ecb04493bc3f8dee993d1132
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GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil

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